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image of Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction of Oxindole-Based Hybrids for the Treatment of Tuberculosis

Abstract

Introduction

With a projected mortality toll of 1.4 million in 2019, tuberculosis (TB) continues to be a significant public health concern around the world. Studies of novel treatments are required due to decreased bioavailability, increased toxicity, increased side effects, and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide.

Methods

This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors targeting Mycobacterium tuberculosis. The synthesized compounds (5a-5e and 8a-8c) were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis and nontuberculous mycobacteria (NTMs), viz. M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841), and M. chelonae (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular docking studies were performed using AutoDock Vina to explore the binding interactions of these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological studies were conducted to assess the hepatotoxicity of the lead compounds. molecular properties and ADMET properties of the synthesized compounds were predicted using SwissADME and Deep-PK online tools to assess their drug-likeness.

Results

Among the tested compounds, 8b exhibited significant anti-mycobacterial activity with a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol. Further, the compound demonstrated a binding affinity and orientation similar to the reference inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal’s interactions. Besides, the compounds hepatotoxicity assessment studies depicted that 8b showed no significant liver dysfunction or damage to liver tissues. Additionally, 8b adhered to Lipinski’s rule of five and Veber’s rule, displaying favourable pharmacokinetic and drug-like properties, including high human intestinal absorption, distribution, and acceptable metabolic stability and excretion.

Conclusion

Compound 8b emerged as a promising candidate for further optimization and development as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.

© 2024 Bentham Science Publishers
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2024-10-31
2025-04-06

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References

  1. Nusrath Unissa A. Hanna L.E. Swaminathan S. A note on derivatives of isoniazid, rifampicin, and pyrazinamide showing activity against resistant Mycobacterium tuberculosis. Chem. Biol. Drug Des. 2016 87 4 537 550 10.1111/cbdd.12684
    [Google Scholar]
  2. Global Tuberculosis report 2023. Available from:https://cdn.who.int/media/docs/default-source/hq-tuberculosis/global-tuberculosis-report-2023/global-tb-report-2023-factsheet.pdf?sfvrsn=f0dfc8a4_4&download=true(accessed on 8-10-2024)
  3. Global Tuberculosis Report Factsheet 2023. Available from:https://www.who.int/publications/m/item/global-tuberculosis-report-factsheet-2023(accessed on 8-10-2024)
  4. Grange J.M. Zumla A. The global emergency of tuberculosis: what is the cause? J. R. Soc. Promot. Health 2002 122 2 78 81 10.1177/146642400212200206
    [Google Scholar]
  5. Bhowmik D. Chiranjib R.M. Jayakar B. Kumar K.P.S. Recent trends of drug used treatment of tuberculosis. J. Chem. Pharm. Res. 2009 1 1 113 133
    [Google Scholar]
  6. Lalloo U.G. Ambaram A. New antituberculous drugs in development. Curr. HIV/AIDS Rep. 2010 7 3 143 151 10.1007/s11904‑010‑0054‑4
    [Google Scholar]
  7. Greenblatt D.J. Elimination half-life of drugs: Value and limitations. Annu. Rev. Med. 1985 36 1 421 427 10.1146/annurev.me.36.020185.002225
    [Google Scholar]
  8. Schraufnagel D. Abubaker J. Global action against multidrug-resistant tuberculosis. JAMA 2000 283 1 54 55 10.1001/jama.283.1.54
    [Google Scholar]
  9. Jones D. Tuberculosis success. Nat. Rev. Drug Discov. 2013 12 3 175 176 10.1038/nrd3957
    [Google Scholar]
  10. Hoagland D.T. Liu J. Lee R.B. Lee R.E. New agents for the treatment of drug-resistant Mycobacterium tuberculosis. Adv. Drug Deliv. Rev. 2016 102 55 72 10.1016/j.addr.2016.04.026
    [Google Scholar]
  11. Coninx R. Mathieu C. Debacker M. Mirzoev F. Ismaelov A. de Haller R. Meddings D.R. First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Lancet 1999 353 9157 969 973 10.1016/S0140‑6736(98)08341‑X
    [Google Scholar]
  12. Langbang A. Deka N. Rahman H. Kalita D. A study on bacterial pathogens causing secondary infections in patients suffering from tuberculosis and their pattern of antibiotic sensitivity. Int. J. Curr. Microbiol. Appl. Sci. 2016 5 8 197 203 10.20546/ijcmas.2016.508.021
    [Google Scholar]
  13. Cohen J. Approval of novel TB drug celebrated—with restraint. Science 2013 339 6116 130 10.1126/science.339.6116.130
    [Google Scholar]
  14. Ryan N.J. Lo J.H. Delamanid: First global approval. Drugs 2014 74 9 1041 1045 10.1007/s40265‑014‑0241‑5
    [Google Scholar]
  15. Ma Z. Lienhardt C. McIlleron H. Nunn A.J. Wang X. Global tuberculosis drug development pipeline: the need and the reality. Lancet 2010 375 9731 2100 2109 10.1016/S0140‑6736(10)60359‑9
    [Google Scholar]
  16. Villemagne B. Crauste C. Flipo M. Baulard A.R. Déprez B. Willand N. Tuberculosis: The drug development pipeline at a glance. Eur. J. Med. Chem. 2012 51 1 16 10.1016/j.ejmech.2012.02.033
    [Google Scholar]
  17. Al-Mudhafar M.M.J. Omar T.N-A. Abdulhadi S.L. J. Pharm. Sci. 2022 22 1 23 48
    [Google Scholar]
  18. Xu Y. Guan J. Xu Z. Zhao S. Design, synthesis and in vitro anti-mycobacterial activities of homonuclear and heteronuclear bis-isatin derivatives. Fitoterapia 2018 127 383 386 10.1016/j.fitote.2018.03.018
    [Google Scholar]
  19. Akhaja T.N. Raval J.P. Design, synthesis, in vitro evaluation of tetrahydropyrimidine–isatin hybrids as potential antibacterial, antifungal and anti-tubercular agents. Chin. Chem. Lett. 2012 23 4 446 449 10.1016/j.cclet.2012.01.040
    [Google Scholar]
  20. Aboul-Fadl T. Mohammed F.A.H. Hassan E.A.S. Synthesis, antitubercular activity and pharmacokinetic studies of some schiff bases derived from 1- alkylisatin and isonicotinic acid hydrazide (inh). Arch. Pharm. Res. 2003 26 10 778 784 10.1007/BF02980020
    [Google Scholar]
  21. Gao F. Yang H. Lu T. Chen Z. Ma L. Xu Z. Schaffer P. Lu G. Design, synthesis and anti-mycobacterial activity evaluation of benzofuran-isatin hybrids. Eur. J. Med. Chem. 2018 159 277 281 10.1016/j.ejmech.2018.09.049
    [Google Scholar]
  22. Chen R. Zhang H. Ma T. Xue H. Miao Z. Chen L. Shi X. Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design, synthesis, and in vitro anti-mycobacterial activity evaluation. Bioorg. Med. Chem. Lett. 2019 29 18 2635 2637 10.1016/j.bmcl.2019.07.041
    [Google Scholar]
  23. Han Y.J. Wang L. Li Q.B. Xue L.W. Synthesis, crystal structure, and antibacterial activity of oxovanadium(V) complexes derived from N′-[1-(5-fluoro-2-hydroxyphenyl)methylidene]nicotinohydrazide and N′-(5-fluoro-2-hydroxybenzylidene)-2-hydroxynaphthylhydrazide. Russ. J. Coord. Chem. 2017 43 9 612 618 10.1134/S1070328417090020
    [Google Scholar]
  24. Soliman D.H. Eldehna W.M. Ghabbour H.A. Kabil M.M. Abdel-Aziz M.M. Abdel-Aziz H.A-K. Novel 6-phenylnicotinohydrazide derivatives: Design, synthesis and biological evaluation as a novel class of antitubercular and antimicrobial agents. Biol. Pharm. Bull. 2017 40 11 1883 1893 10.1248/bpb.b17‑00361
    [Google Scholar]
  25. Castelo-Branco F.S. de Lima E.C. Domingos J.L.O. Pinto A.C. Lourenço M.C.S. Gomes K.M. Costa-Lima M.M. Araujo-Lima C.F. Aiub C.A.F. Felzenszwalb I. Costa T.E.M.M. Penido C. Henriques M.G. Boechat N. New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity. Eur. J. Med. Chem. 2018 146 529 540 10.1016/j.ejmech.2018.01.071
    [Google Scholar]
  26. Aboul-Fadl T. Abdel-Aziz H.A. Kadi A. Ahmad P. Elsaman T. Attwa M.W. Darwish I.A. Microwave-assisted solution-phase synthesis and DART-mass spectrometric monitoring of a combinatorial library of indolin-2,3-dione schiff bases with potential antimycobacterial activity. Molecules 2011 16 6 5194 5206 10.3390/molecules16065194
    [Google Scholar]
  27. Aboul-Fadl T. Bin-Jubair F.A.S. Aboul-Wafa O. Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur. J. Med. Chem. 2010 45 10 4578 4586 10.1016/j.ejmech.2010.07.020
    [Google Scholar]
  28. Abo-Ashour M.F. Eldehna W.M. George R.F. Abdel-Aziz M.M. Elaasser M.M. Abdel Gawad N.M. Gupta A. Bhakta S. Abou-Seri S.M. Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents. Eur. J. Med. Chem. 2018 160 49 60 10.1016/j.ejmech.2018.10.008
    [Google Scholar]
  29. Banerjee A. Dubnau E. Quemard A. Balasubramanian V. Um K.S. Wilson T. Collins D. de Lisle G. Jacobs W.R. Jr inhA, a Gene Encoding a Target for Isoniazid and Ethionamide in Mycobacterium tuberculosis. Science 1994 263 5144 227 230 10.1126/science.8284673
    [Google Scholar]
  30. Modi P. Patel S. Chhabria M.T. Identification of some novel pyrazolo[1,5- a ]pyrimidine derivatives as InhA inhibitors through pharmacophore-based virtual screening and molecular docking. J. Biomol. Struct. Dyn. 2019 37 7 1736 1749 10.1080/07391102.2018.1465852
    [Google Scholar]
  31. Takayama K. Wang C. Besra G.S. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin. Microbiol. Rev. 2005 18 1 81 101 10.1128/CMR.18.1.81‑101.2005
    [Google Scholar]
  32. Zhang Y. Heym B. Allen B. Young D. Cole S. The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 1992 358 6387 591 593 10.1038/358591a0
    [Google Scholar]
  33. Wang F. Langley R. Gulten G. Dover L.G. Besra G.S. Jacobs W.R. Jr Sacchettini J.C. Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med. 2007 204 1 73 78 10.1084/jem.20062100
    [Google Scholar]
  34. He X. Alian A. Ortiz de Montellano P.R. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg. Med. Chem. 2007 15 21 6649 6658 10.1016/j.bmc.2007.08.013
    [Google Scholar]
  35. Abdel-Aal W.S. Hassan H.Y. Aboul-Fadl T. Youssef A.F. Pharmacophoric model building for antitubercular activity of the individual Schiff bases of small combinatorial library. Eur. J. Med. Chem. 2010 45 3 1098 1106 10.1016/j.ejmech.2009.12.005
    [Google Scholar]
  36. Aboul-Fadl T. Bin-Jubair F.A.S. Int. J. Res. Pharm. Sci. 2010 1 113 126
    [Google Scholar]
  37. Franzblau S.G. Witzig R.S. McLaughlin J.C. Torres P. Madico G. Hernandez A. Degnan M.T. Cook M.B. Quenzer V.K. Ferguson R.M. Gilman R.H. Rapid, Low-Technology MIC Determination with Clinical Mycobacterium tuberculosis Isolates by Using the Microplate Alamar Blue Assay. J. Clin. Microbiol. 1998 36 2 362 366 10.1128/JCM.36.2.362‑366.1998
    [Google Scholar]
  38. Cho S. Lee H.S. Franzblau S. Mycobacteria Protocols, Methods in Molecular Biology. Parish T. Roberts S. New York, NY Humana Press 2015 1285
    [Google Scholar]
  39. Siddiqui N. Rana A. Khan S.A. Bhat M.A. Haque S.E. Synthesis of benzothiazole semicarbazones as novel anticonvulsants—The role of hydrophobic domain. Bioorg. Med. Chem. Lett. 2007 17 15 4178 4182 10.1016/j.bmcl.2007.05.048
    [Google Scholar]
  40. Luna L.G. Manual of Histological Staining Methods of the Armed Forces Institute of Pathology. New York McGraw-Hill 1968 567 568
    [Google Scholar]
  41. Morris G.M. Huey R. Lindstrom W. Sanner M.F. Belew R.K. Goodsell D.S. Olson A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009 30 16 2785 2791 10.1002/jcc.21256
    [Google Scholar]
  42. Trott O. Olson A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010 31 2 455 461 10.1002/jcc.21334
    [Google Scholar]
  43. Eberhardt J. Santos-Martins D. Tillack A.F. Forli S. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings. J. Chem. Inf. Model. 2021 61 8 3891 3898 10.1021/acs.jcim.1c00203
    [Google Scholar]
  44. Patel V.P. Tripathi R.K.P. Dharamsi A. Computational exploration of isatin derivatives for inha inhibition in tuberculosis: molecular docking, MD simulations and ADMET insights Curr. Comput. Aided. Drug Des. 2024 Online ahead of Print 10.2174/0115734099333313240909103833
    [Google Scholar]
  45. Kumari R. Dalal V. Identification of potential inhibitors for LLM of Staphylococcus aureus : structure-based pharmacophore modeling, molecular dynamics, and binding free energy studies. J. Biomol. Struct. Dyn. 2022 40 20 9833 9847 10.1080/07391102.2021.1936179
    [Google Scholar]
  46. Kumari R. Rathi R. Pathak S.R. Dalal V. Structural-based virtual screening and identification of novel potent antimicrobial compounds against YsxC of Staphylococcus aureus. J. Mol. Struct. 2022 1255 132476 10.1016/j.molstruc.2022.132476
    [Google Scholar]
  47. Tripathi R.K.P. Dey R. Das N. Identification of natural lead molecules as potential Trypanosoma cruzi cruzipain inhibitors and decoding the interaction mechanism for the treatment of Chagas disease: A computational biology analysis. Nat. Prod. Res. 2024 38 20 3676 3680 10.1080/14786419.2023.2256018
    [Google Scholar]
  48. Tian S. Wang J. Li Y. Li D. Xu L. Hou T. The application of in silico drug-likeness predictions in pharmaceutical research. Adv. Drug Deliv. Rev. 2015 86 2 10 10.1016/j.addr.2015.01.009
    [Google Scholar]
  49. Khan T. Lawrence A.J. Azad I. Raza S. Joshi S. Khan A.R. Abdul R. Computational drug designing and prediction of important parameters using in silico methods- a review. Curr. Computeraided Drug Des. 2019 15 5 384 397 10.2174/1573399815666190326120006
    [Google Scholar]
  50. Chandrasekaran B. Abed S.N. Al-Attraqchi O. Kuche K. Tekade R.K. Advances in pharmaceutical product development and research. Dosage Form Design Parameters Academic Press 2018
    [Google Scholar]
  51. Panchal I. Tripathi R.K.P. Yadav M.R. Valera M. Parmar K. Design, synthesis, and biological and in silico evaluation of novel indazole-pyridine hybrids for the treatment of breast cancer. Curr. Comput. Aided. Drug Des. 2024 Online ahead of Print 10.2174/0115734099308839240724100224
    [Google Scholar]
  52. SWISSadme. Available from:http://www.swissadme.ch/(accessed on 8-10-2024)
  53. deep learning for small molecule pharmacokinetic and toxicity prediction. Available from:https://biosig.lab.uq.edu.au/deeppk/(accessed on 8-10-2024)
  54. Boström J. Greenwood J.R. Gottfries J. Assessing the performance of OMEGA with respect to retrieving bioactive conformations. J. Mol. Graph. Model. 2003 21 5 449 462 10.1016/S1093‑3263(02)00204‑8
    [Google Scholar]
  55. Dassault systèmes virtual worlds help you improve real life. 2019 Available from:https://www.3ds.com/(accessed on 8-10-2024)
  56. Lipinski C.A. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Adv. Drug Deliv. Rev. 2016 101 34 41 10.1016/j.addr.2016.04.029
    [Google Scholar]
  57. Veber D.F. Johnson S.R. Cheng H.Y. Smith B.R. Ward K.W. Kopple K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002 45 12 2615 2623 10.1021/jm020017n
    [Google Scholar]
  58. Daina A. Michielin O. Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017 7 1 42717 10.1038/srep42717
    [Google Scholar]
  59. Olasupo S.B. Uzairu A. Adamu G.S. Uba S. Computational modeling and pharmacokinetics/admet study of some arylpiperazine derivatives as novel antipsychotic agents targeting depression. Chem. Africa 2020 3 4 979 988 10.1007/s42250‑020‑00161‑4
    [Google Scholar]
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Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction of Oxindole-Based Hybrids for the Treatment of Tuberculosis
Bentham Science Publishers ; https://doi.org/10.2174/0115734099353857241022102426
/content/journals/cad/10.2174/0115734099353857241022102426
/content/journals/cad/10.2174/0115734099353857241022102426
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  • Article Type:     Research Article
Keywords: ADMET ; hepatotoxicity studies ; oxindole-based hybrids ; Tuberculosis ; molecular docking ; InhA inhibitors

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